This Project centers on the VCRC Genetics and Genomics Program and includes a broad range of individual scientific projects exploring i) the genetic basis of vasculitis in terms of disease susceptibility, clinical expression and outcome, and response to treatment; ii) the molecular pathophysiology of vasculitis; and iii) potential biomarkers useful for the management of these complex diseases. The recent history of genetics research in rare diseases makes it clear that only through collaboration and cooperation can study populations of meaningful sizes be assembled to conduct genome-wide association studies. The VCRC has established productive collaborations within the international vasculitis communities to conduct such shared genetic research, and also to conduct candidate gene studies and to perform exome sequencing to identify genes containing rare variants. Genomic DNA has been obtained from the > 1700 patients already enrolled in VCRC studies, and that number will increase greatly during the next 5 years. Gene expression profiling and epigenetics provide complementary insights into the pathophysiology of disease and can also be used to identify biomarkers of important clinical outcomes. RNA already collected from two VCRC clinical trials will be analyzed for this purpose. The existing protocols for sample collection in the VCRC Longitudinal Studies can easily be adapted to collect DNA (epigenetics) and RNA (gene expression) longitudinally. The Specific Aims of this Project are to: 1) continue to collect genomic DNA and linked comprehensive clinical data from patients with multiple forms of vasculitis to conduct large-scale collaborative genetics studies; 2) conduct a series of candidate gene analyses and genome-wide association studies; 3) conduct studies of exome sequencing in order to identify genes with rare variants associated with risk of vasculitis; 4) study gene expression profiles from the whole blood of patients with vasculitis during active disease and remission, to identify signatures and molecular pathways related to disease activity, response to therapy, and/or long-term prognosis; and 5) study DNA methylation patterns (epigenetics) in white blood cells to gain insight into pathophysiology of vasculitis and to investigate another potential source of biomarkers useful for diagnosis or prognosis.